EP1986651B1 - Utilisation d'un dérivé de pyrimidinedione permettant la prévention et le traitement de l'hépatite c - Google Patents

Utilisation d'un dérivé de pyrimidinedione permettant la prévention et le traitement de l'hépatite c Download PDF

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Publication number
EP1986651B1
EP1986651B1 EP07708838A EP07708838A EP1986651B1 EP 1986651 B1 EP1986651 B1 EP 1986651B1 EP 07708838 A EP07708838 A EP 07708838A EP 07708838 A EP07708838 A EP 07708838A EP 1986651 B1 EP1986651 B1 EP 1986651B1
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EP
European Patent Office
Prior art keywords
dione
pyrimidine
dimethyl
isopropyl
cyclopent
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Not-in-force
Application number
EP07708838A
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German (de)
English (en)
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EP1986651A4 (fr
EP1986651A1 (fr
Inventor
Ho-Seok Kwon
Jae-Woong Lee
Sun-Hwan Lee
Young-Hee Lee
Jeong-Ho Joo
Sun-Gan Chung
Hyun-Tae Kim
Eui-Hwan Cho
Hyun-Nam Myung
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Samjin Pharmaceutical Co Ltd
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Samjin Pharmaceutical Co Ltd
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Publication of EP1986651B1 publication Critical patent/EP1986651B1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65G—TRANSPORT OR STORAGE DEVICES, e.g. CONVEYORS FOR LOADING OR TIPPING, SHOP CONVEYOR SYSTEMS OR PNEUMATIC TUBE CONVEYORS
    • B65G49/00—Conveying systems characterised by their application for specified purposes not otherwise provided for
    • B65G49/05—Conveying systems characterised by their application for specified purposes not otherwise provided for for fragile or damageable materials or articles
    • B65G49/06—Conveying systems characterised by their application for specified purposes not otherwise provided for for fragile or damageable materials or articles for fragile sheets, e.g. glass
    • B65G49/061—Lifting, gripping, or carrying means, for one or more sheets forming independent means of transport, e.g. suction cups, transport frames
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65G—TRANSPORT OR STORAGE DEVICES, e.g. CONVEYORS FOR LOADING OR TIPPING, SHOP CONVEYOR SYSTEMS OR PNEUMATIC TUBE CONVEYORS
    • B65G2201/00—Indexing codes relating to handling devices, e.g. conveyors, characterised by the type of product or load being conveyed or handled
    • B65G2201/02—Articles
    • B65G2201/0214—Articles of special size, shape or weigh
    • B65G2201/022—Flat
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65G—TRANSPORT OR STORAGE DEVICES, e.g. CONVEYORS FOR LOADING OR TIPPING, SHOP CONVEYOR SYSTEMS OR PNEUMATIC TUBE CONVEYORS
    • B65G2249/00—Aspects relating to conveying systems for the manufacture of fragile sheets
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65G—TRANSPORT OR STORAGE DEVICES, e.g. CONVEYORS FOR LOADING OR TIPPING, SHOP CONVEYOR SYSTEMS OR PNEUMATIC TUBE CONVEYORS
    • B65G47/00—Article or material-handling devices associated with conveyors; Methods employing such devices
    • B65G47/74—Feeding, transfer, or discharging devices of particular kinds or types
    • B65G47/88—Separating or stopping elements, e.g. fingers
    • B65G47/8807—Separating or stopping elements, e.g. fingers with one stop
    • B65G47/883—Fixed stop
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65G—TRANSPORT OR STORAGE DEVICES, e.g. CONVEYORS FOR LOADING OR TIPPING, SHOP CONVEYOR SYSTEMS OR PNEUMATIC TUBE CONVEYORS
    • B65G47/00—Article or material-handling devices associated with conveyors; Methods employing such devices
    • B65G47/74—Feeding, transfer, or discharging devices of particular kinds or types
    • B65G47/90—Devices for picking-up and depositing articles or materials
    • B65G47/91—Devices for picking-up and depositing articles or materials incorporating pneumatic, e.g. suction, grippers
    • B65G47/912—Devices for picking-up and depositing articles or materials incorporating pneumatic, e.g. suction, grippers provided with drive systems with rectilinear movements only
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65G—TRANSPORT OR STORAGE DEVICES, e.g. CONVEYORS FOR LOADING OR TIPPING, SHOP CONVEYOR SYSTEMS OR PNEUMATIC TUBE CONVEYORS
    • B65G49/00—Conveying systems characterised by their application for specified purposes not otherwise provided for
    • B65G49/05—Conveying systems characterised by their application for specified purposes not otherwise provided for for fragile or damageable materials or articles
    • B65G49/06—Conveying systems characterised by their application for specified purposes not otherwise provided for for fragile or damageable materials or articles for fragile sheets, e.g. glass
    • B65G49/068—Stacking or destacking devices; Means for preventing damage to stacked sheets, e.g. spaces

Definitions

  • the present invention relates to a use of a pyrimidinedione derivative or a pharmaceutically acceptable salt thereof for preventing or treating hepatitis C.
  • Hepatitis C caused by hepatitis C virus (HCV) infection has been extensively studied in the last two decades, but it still remains difficult to treat due to incomplete information on HCV.
  • HCV hepatitis C virus
  • Ribavirin approved by Food and Drug Administration (FDA) for treating hepatitis C ( Thomas et al., Hepatology 20(4):440, 1994 ), which is a purine nucleoside derivative.
  • FDA Food and Drug Administration
  • Interferon- ⁇ having antiviral activity against a wide spectrum of DNA and RNA viruses has been suggested as a therapeutic for hepatitis C. However, they are considered to be inappropriate for clinical application due to serious side effects and their low curative effect.
  • pyrimidinedione derivatives have been developed for use as an antiviral agent for treating AIDS.
  • Korean Patent Laid-open Publication 2000-65885 discloses novel pyrimidinedione derivatives sinthesized by introducing a homocyclic, or alky or alkylcarbonylmethy group to the N-1 site of pyrimidinedione.
  • the disclosure suggests that said pyrimidinedione derivatives have strong pharmacological activity against human immunodeficiency virus (HIV) in the absence of tonicity.
  • HAV human immunodeficiency virus
  • US 2005009737 refers to the use of (2'R)-2'-deoxy-2'-fluoro-2'-C-methylcytidine (not falling under general formula I of present application) in the prevention/treatment of hepatitis C virus infection.
  • Bovine viral diarrhea virus (BVDV) is a pestivirus belonging to the family of Flaviviridae and has been used as a surrogate to study the HCV. We have unexpectedly found that such pyrimidinedione derivatives are effective in preventing or treating hepatitis C.
  • the preferable pyrimidinedione derivative of formula (I) that maybe used in the present invention is a corresponding compound wherein R 1 is C 3 ⁇ C 6 cycloalkyl, cyclopentenyl or hydroxymethylcyclopentenyl.
  • the pyrimidinedione derivative for use in the present invention can be prepared by the method described in Korean Patent Laid-open Publication No. 2000-65885 .
  • pyrimidinedione derivative for use in the present invention is prepared according to the following reaction scheme:
  • R 1 to R 4 , X and n have the same meanings as defined in formula (I), and Lie means a leaving group, e.g. halogen, alkylsulfonyl and arylsulfonyl.
  • the compound of formula (II) used as the starting material in the reaction scheme can be prepared by a conventional method, e.g. WO 93/02044 and WO 95/18109 .
  • the pyrimidinedione derivative of formula (I) can be prepared by allowing the compound of formula (II) to react with the compound of formula (III) in the presence of a base.
  • the equivalent ratio of the compounds of formula (II) and formula (III) preferably is in the range of 1:0.8 to 1:1.5.
  • the base used in the above reaction may be selected from the group consisting of anhydrous sodium hydrogen carbonate, anhydrous sodium carbonate, sodium hydride, potassium carbonate and a mixture thereof; and the organic slovent used therefor may be a polar solvent such as dimethylformamide, acetonitrile, dimethylsulfoxide and a mixture thereof.
  • the reaction may be carried out at 10 to 100 °C for 1 to 48 hours.
  • the pyrimidinedione derivative used in the present invention may be in the form of a pharmaceutically acceptable salt prepared by reacting a pyrimidinedione derivative (I) of formula with an inorganic or organic acid, or a base.
  • the acid may include an organic acid such as hydrochloric acid and sulphuric acid, and an inorganic acid such as acetic acid and maleic acid.
  • the base may include alkali or alkali earth metals such as sodium, potassium, magnesium and calcium.
  • a pyrimidinedione derivative or a pharmaceutically acceptable salt thereof can be advantageously used for preventing or treating hepatitis C due to its capability to inhibit the activity of hepatitis C virus to an extent which is higher than the Ribavirin.
  • the present invention provides a pharmaceutical composition for preventing or treating hepatitis C comprising a pyrimidinedione derivative of formula (I) or a pharmaceutically accepatable salt thereof as an active ingredient, preferably, in combination with a pharmaceutically acceptable carrier or additive.
  • a pharmaceutical formulation may be prepared in accordance with any of the conventional procedures.
  • the active ingredient is preferably admixed or diluted with a carrier, or enclosed within a carrier, sachet or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid or liquid material acting as a vehicle, excipient or medium for the active ingredient.
  • the formulations may be in the form of a tablet, pill, powder, sachet, elixir, suspension, emulsion, solution, syrup, aerosol, soft and hard gelatin capsule, sterile injectable solution, sterile packaged powder and the like.
  • Suitable carriers, excipients, and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoates, propylhydroxybenzoates, talc, magnesium stearate and mineral oil.
  • the formulations may additionally include fillers, anti-agglutinating agents, lubricating agents, wetting agents, flavoring agents, emulsifiers, preservatives and the like.
  • the composition of the present invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after their administration to a mammal by employing any of the procedures well known in the art.
  • the present invention provides a method for preventing or treating hepatitis C in a mammal, which comprises administering the pyrimidinedione derivative of formula (I) to the mammal.
  • the dosage of the active ingredient may be adjusted in light of various relevant factors such as the condition of the subject to be treated, type and seriousness of illness, administration rate, and opinion of doctor.
  • the compound of formula (I) can be administered orally or parenterally in an effective amount ranging from about 1 to 100 mg/kg (body weight), preferably 5 to 50 mg/kg (body weight) per day in case of a mammal including a human being in a single dose or in divided doses. In certain cases, an amount less than the above dosage may be suitable. An amount greater than the above dosage may be used unless it causes deleterious side effects, and such amount can be administered in divided doses per day.
  • BVDV bovine viral diarrhea virus
  • MDBK cell line (Mardin-Darby bovine kidney, ATTC CCL22) which had been subcltured previously was trypsinized and spread on a plate, followed by counting the cell colonies formed. Then, equal amount of DMEM (Dulbecco's Modified Eagle's Medium) and Ham's F-12 were mixed, and 10 % fetal bovine serum was added to the resulting mixture to prepare a tissue culture medium. The MDBK cells were inoculated to the medium at a concentration of 6 ⁇ 10 4 cells/ml, and then the resulting cell solution was added to a 96-well flat-bottommed plate in an amount of 100 ⁇ l per well.
  • DMEM Dynamic fetal bovine serum
  • BVDV(ATCC VR534) which had been stored in a -80 °C freezer at a pre-determined concentration, was transferred to a biological safty cabinet and allowed to thaw at room temperature.
  • the virus was diluted with the tissue culture medium in an sufficient amount for the virus in each well to induce 85 to 95 % cell death 6 days after the virus infection.
  • SAMJIN Pharmaceuticals Specified pyrimidinedione derivatives
  • a conventional drug for treating hepatitis C, Ribavirin (Sigma) was used as a comparative drug.
  • Each of the test compounds was desolved in DMSO to prepare a sample solution. Then, the resulting sample solution was diluted with a mixture prepared by mixing equal amount of DMEM and Ham's F-12 in accordance with the three one-log series dilution to prepare sample dilutes.
  • the culture solution on the plate was removed and each of the sample dilutes obtained step 2 was added thereto, adjusting the final concentration thereof to 1 to 100 ⁇ g/ml.
  • the comparative drug, Ribavirin was added to each of the control wells of the palte at a concentration of 1 to 100 ⁇ g/ml.
  • the well-plate comprising 'cell control group well' containing MDBK cell only; 'virus control well' containing MDBK cell and BVDV virus; 'drug toxicity control well' containing MDBK cell and sample compounds for assessing the cell toxicity of each sample; 'drug colorimetric control well' containing only one of the sample compounds; and 'experimental group well' containing MDBK cell, BVDV virus and one of the sample compounds.
  • the well-plate had been placed in a 5 % CO 2 incubator at 37 °C for 6 days, and then, analyzed with Cell Proliferation Assay kit (CellTiter96 ® AQ UEOUS one solution, Promega).
  • CellTiter96 ® AQ UEOUS one solution Promega.
  • the analysis involves the step of counting live cells by a colorimetric method and the kit contains MTS, a new tetrazolium compound which forms a stable solution when the test compounds are added, and PES, an electron coupling agent.
  • MTS Cell Proliferation Assay kit
  • PES an electron coupling agent.
  • NADPH or NADH generated by mitochodrial dehydrogenase renders the soluble MTS to a form of insoluble formazan crystals. Therefore, the amount of formazan crystal is directly proportional to the number of live cells in a medium.
  • the CellTiter96 ® AQ UEOUS one solution reagent of 10 ⁇ l was added to each well of the plate and cultivated in a incubator at 37 °C for 4 hours. Then, the plate was covered with an adhesive plate sealer, mixing formazan crystals. Absorbance of each well was measured by Molecular Devices Vmax plate reader (Molecular Devices) at 490 nm.
  • EC 50 means the dosage at which the desired response is present for 50 % of the population, i.e., the concentration of the sample compounds at which the BVDV infection was inhibited for 50 % of MDBK cells;
  • TC 50 means the dosage at which cell death is induced for 50 % of the population, i.e., the cytotoxicity of the sample compounds for MDBK cells.
  • TI TC 50 /EC 50 ) means a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxic effects. Quantitatively, it is the ratio given by the dose required to produce the toxic effect divided by the therapeutic dose.
  • a pyrimidinedione derivative according to the present invention showed similar or superior TI value to the control drug, Ribavirin, implying that they can be used for preventing or treating hepatitis C.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un dérivé de pyrimidinedione de formule (I) ou un sel pharmaceutiquement acceptable de ce dérivé présentant une excellente activité inhibitrice vis-à-vis du virus de l'hépatite C.

Claims (3)

  1. Dérivé de pyrimidinedione de formule (I) :
    Figure imgb0021
     où,
    R1 représente un groupe cycloalkyle en C3~C6 ou cycloalcényle en C3~C6 éventuellement substitué par au moins un groupe hydroxy(alkyle en C1~C4) X représente un atome d'oxygène, un atome de soufre ou un groupe carbonyle ; n vaut 1 ou 2 ; et
    R2, R3 et R4 représentent chacun indépendamment un atome d'hydrogène ou un groupe alkyle en C1~C4, destiné à être utilisé dans la prévention ou le traitement de l'hépatite C.
  2. Dérivé de pyrimidinedione selon la revendication 1 destiné à être utilisé conformément à la revendication 1, dans lequel R1 représente un groupe cycloalkyle en C3~C6, cyclopentényle ou hydroxyméthylcyclopentényle.
  3. Dérivé de pyrimidinedione selon la revendication 1 destiné à être utilisé conformément à la revendication 1, ledit dérivé de pyrimidinedione étant choisi dans le groupe constitué des composés suivants :
    1) 1-cyclopropylméthyl-6-(3,5-diméthyl-phénylsulfanyl)-5-isopropyl-1H-pyrimidine-2,4-dione ;
    2) 1-cyclopropylméthyl-6-(3,5-diméthyl-phénoxy)-5-éthyl-1H-pyrimidine-2,4-dione ;
    3) 1-cyclobutylméthyl-6-(3,5-diméthyl-phénylsutfanyl)-5-isopropyl-1H-pyrimidine-2,4-dione ;
    4) 1-cyclopentylméthyl-6-(3,5-diméthyl-phénylsulfanyl)-5-isopropyl-1H-pyrimidine-2,4-dione ;
    5) 1-cyclopent-1-énylméthyl-6-(3,5-diméthyl-phénylsulfanyl)-5-isopropyl-1H-pyrimidine-2,4-dione ;
    6) 1-cyclopent-1-énylméthyl-6-(3,5-diméthyl-phénoxy)-5-éthyl-1H-pyrimidine-2,4-dione ;
    7) 1-cydopent-1-énylméthyl-6-(3,5-diméthyl-phénoxy)-5-isopropyl-1H-pyrimidine-2,4-dione ;
    8) 1-cyclopent-1-énylméthyl-6-(3,5-diméthyl-benzoyl)-5-éthyl-1H-pyrimidine-2,4-dione ;
    9) 1-cyclopent-1-énylméthyl-6-(3,5-diméthyl-benzoyl)-5-isopropyl-1H-pyrimidine-2,4-dione ;
    10) 1-cyclopent-3-énylméthyl-5-isopropyl-6-phénylsulfanyl-1H-pyrimidine-2,4-dione ;
    11) 1-cyclohexylméthyl-6-(3,5-diméthyl-phénylsulfanyl)-5-isopropyl-1H-pyrimidine-2,4-dione ;
    12) 1-(2-cyclopentyl-éthyl)-6-(3,5-diméthyl-phénylsulfanyl)-5-isopropyl-1H-pyrimidine-2,4-dione ;
    13) 1-(2-cyclopent-2-ényl-éthyl)-6-(3,5-diméthyl-phénoxy)-5-isopropyl-1H-pyrimidine-2,4-dione ;
    14) 1-(2-cyclopent-3-ényl-éthyl)-6-(3,5-diméthyl-phénylsulfanyl)-5-éthyl-1H-pyrimidine-2,4-dione ;
    15) 1-(2-cyclopent-2-ényl-éthyl)-6-(3,5-diméthyl-benzoyl)-5-isopropyl-1H-pyrimidine-2,4-dione ; et
    16) 6-(3,5-diméthyl-benzoyl)-5-éthyl-1-(4-hydroxyméthyl-cyclopent-1-énylméthyl)-1H-pyrimidine-2,4-dione.
EP07708838A 2006-02-10 2007-02-08 Utilisation d'un dérivé de pyrimidinedione permettant la prévention et le traitement de l'hépatite c Not-in-force EP1986651B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020060013037A KR101237312B1 (ko) 2006-02-10 2006-02-10 피리미딘다이온 유도체를 포함하는 ｃ형 간염의 예방 및치료용 약학 조성물
PCT/KR2007/000688 WO2007091857A1 (fr) 2006-02-10 2007-02-08 Utilisation d'un dérivé de pyrimidinedione permettant la prévention et le traitement de l'hépatite c

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EP1986651A1 EP1986651A1 (fr) 2008-11-05
EP1986651A4 EP1986651A4 (fr) 2010-02-17
EP1986651B1 true EP1986651B1 (fr) 2011-10-05

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Country Status (7)

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US (1) US7851479B2 (fr)
EP (1) EP1986651B1 (fr)
JP (1) JP5043868B2 (fr)
KR (1) KR101237312B1 (fr)
CN (1) CN101384262B (fr)
CA (1) CA2642136C (fr)
WO (1) WO2007091857A1 (fr)

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MY161170A (en) * 2011-03-18 2017-04-14 Corcept Therapeutics Inc Pyrimidine cyclohexyl glucocorticoid receptor modulators

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KR100368891B1 (ko) * 1999-03-04 2003-01-24 한국화학연구원 신규한 항바이러스성 2,4-피리미딘디온 유도체
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Cited By (3)

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Publication number Priority date Publication date Assignee Title
RU2595868C1 (ru) * 2015-03-27 2016-08-27 Виктор Вениаминович Тец Лекарственное средство с гепатопротекторной активностью
WO2016159833A1 (fr) * 2015-03-27 2016-10-06 Виктор Вениаминович ТЕЦ Médicament à action hépatoprotectrice
US10307424B2 (en) 2015-03-27 2019-06-04 Georgy Viktorovich Tets Drug with hepatoprotective activity

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CN101384262B (zh) 2011-05-04
CA2642136C (fr) 2011-01-04
CN101384262A (zh) 2009-03-11
EP1986651A4 (fr) 2010-02-17
CA2642136A1 (fr) 2007-08-16
KR20070081238A (ko) 2007-08-16
US20090023764A1 (en) 2009-01-22
US7851479B2 (en) 2010-12-14
KR101237312B1 (ko) 2013-03-04
JP2009526041A (ja) 2009-07-16
JP5043868B2 (ja) 2012-10-10
EP1986651A1 (fr) 2008-11-05
WO2007091857A1 (fr) 2007-08-16

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